1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone and a process for preparing the same

ABSTRACT

This invention relates to 1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone. This compound is convertible into 4-(4-methyl thio phenyl)-3-phenyl-2 (5H)-furanone by an economically viable process. This substituted furanone is an intermediate or starting compound for synthesising COX II inhibitor Rofecoxib. This invention also includes a process for preparing the ethanone derivative by halogenating methyl thio aceto phenone and coupling the resulting 2 halosubstituted ethanone with sodium salt of phenyl acetic acid to obtain 1-[(4-methyl thio) phenyl]-2-(phenyl acetoxy)-1-ethanone.

BACKGROUND OF THE INVENTION

Non-steroid, anti-inflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine concentrations and certain types of cancergrowth through the inhibition of prostaglandin G/H synthase, also knownas cyclooxygenase. Until recently, only one form of cyclooxygenease hadbeen characterised, this corresponding to cyclooxygenase I or theconstitutive enzyme, as originally identified in bovine seminalvesicles. Recently the gene for a second inducible form ofcyclooxygenase (cyclooxygenase-2) has been cloned, sequenced andcharacterised from chicken, murine and human sources. This enzyme isdistinct from the cyclooxygenease-1 which has now also been cloned,sequenced and characterised from sheep, murine and human sources. Thesecond form of cyclooxygenase, cyclooxygenase-2 is rapidly and readilyinducible by a number of agents including mitogens, endotoxins,hormones, cytokines and growth factors. As prostaglandines have bothphysiological and pathological roles, it was concluded that theconstitutive enzyme, cyclooxygenase-1, is responsible, in large part,for endogenous basal release of prostaglandins and hence is important intheir physiological functions such as the maintenance ofgastrointestinal integrity and renal blood flow. In contrast it was alsoconcluded that the inducible form of cyclooxygenase-2 is mainlyresponsible for the pathological affects of prostaglandins where rapidinduction of the enzyme would occur in response to such agents asinflammatory agents, hormones, growth factors and cytokines. Thus, aselective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventionalnon-steroidal anti inflammatory drug and in addition would inhibithormone-induced uterine contractions and have potential anti cancereffects but will have a diminished ability to induce some of themechanism based side effects. In particular such a compound should havea reduced potential for gasterointestinal toxicity, a reduced potentialfor renal side effects, a reduced effect on bleeding tomes and possiblya lessened ability to induce attacks of asthma in aspirin-sensitiveasthmatic subjects.

4-(4-methyl thio phenyl)-3-phenyl-2(5H)-furanone of the formula II shownherein below:

is a key intermediate in the preparation of COX-II inhibitor, known inthe art as Rofecoxib which has a structure X given below:

The process known in the art for preparing the intermediate compound ofthe formula II involve tedious multi-step synthesis, utilizing expensivereagents. Therefore, the known synthetic processes for the production ofthe compound of formula II is not economically viable and are not costeffective.

It has now been found that the novel compound of formula I can be usedas a starting material for the production of the compound of formula IIin an economically advantageous manner. Cost-effective preparation ofthis intermediate, no doubt helps in reducing the price line of COX IIinhibitor.

DISCLOSURE OF THE INVENTION

This invention encompasses the novel compound 1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone which are useful in synthesisingan intermediate compound for the production of COX-II inhibitors.

This invention also includes processes for preparing the novel compoundof formula I.

4-methylthio acetophenone of the formula III

may be subjected to side chain halogenation to produce the correspondingphenacyl halide which may be coupled with phenyl acetic acid in thepresence of organic or inorganic bases to produce the compound offormula I. The reaction scheme is shown below:

Side chain halogenation reaction of the compound of formula III may beeffected in polar protic or polar aprotic solvents in the absence of acatalyst. The halogenation reaction solvents may include chloroform,dichloromethane and carbon tetrachloride and polar protic solventsinclude methanol, ethanol and isopropanol. Chloroform and methanol arethe preferred solvents. Use of acid scavengers in the reaction is purelyoptional. The acid scavengers when used may include hydroxides,carbonates and bicarbonates of alkali or alkaline earth metals. Thepreferred acid scavengers are sodium or potassium bicarbonate. Thereaction temperature may range from 0° C. to 20° C. and the preferredrange is 0° C. to 10° C. It is noted that at 0 to 10° C., the productionof the dihalogenated compound is suppressed.

The phenyl halide that separates is filtered and washed with chilledmethanol which is preferably cooled below 5° C. The product hasexcellent purity of 98% and may be used directly for the next step.

Liquid bromine or N-bromo succinamide may be used as the brominatingagents. The molar ratio of the reactants may be in the ratio of1:0.8–1.5-molar equivalents. The preferred range is 1:1.2 molarequivalents. The minimum solvent dilution for carrying out the reactionis in the range of 2–20 times preferably in the range of 5–7 times.

Acid scavengers when used may be in the range of 1–5 times by weight ofthe compound of formula III. The preferred range is 2–3 times.

The thus obtained phenacyl halide of the formula IV is converted intothe compound of formula I by coupling the same with phenylacetic acid inthe presence of organic or inorganic bases. The organic bases include diand tri alkyl amines such as di isopropyl amine, tri ethyl amine and 1,8diazabicyclo [5.4.0] undec-7-ene (DBU). In organic bases includecarbonates and bicarbonates of alkaline, or alkaline earth metals.Sodium and potassium carbonates and bicarbonates are preferred. Thereaction may be effected in the presence of sodium and/or potassiumsalts of phenyl acetic acid. A phase transfer catalyst may optionally beused. The preferred phase transfer catalyst is tetraalkyl ammoniumhalides and tricaprylylmethyl ammonium chloride in polar or non-polarsolvents. The polar solvents include DMF, DMA, N-methyl pyrrolidinone,THF and 1,4 dioxane. The non-polar solvents include, aromatic solventslike benzene, toulene, ethyl benzene, isopropyl benzene and isobutylbenzene. The reaction temperature may range from 40 to 100° C. and thepreferred range is 70° C. to 100° C. The molar ratio of the reactantsnamely the compound of formula IV and the phenyl acetic acid sodium saltis in the range of 1.2 molar equivalents and the preferred range is1:1.0–1.2 molar equivalents. The molar ratio of the compound of formulaIV with the phase transfer catalyst is in the range of 1:0.005 to 0.008molar equivalents. The solvent dilution is generally in the range of5–25 times over the compound of formula IV and may preferably in therange of 10–15 times.

The Intermediate compound of formula II may be obtained from thecompound of formula I by intramolecular knovengal condensation usingorganic or inorganic bases. The preferred organic bases are trialkyl,dialkyl amines, for example triethyl amine, diisopropyl amine, diethylmethylamine and DBU in polar aprotic solvents. The aprotic solventsinclude DMF, DMA, N-Methyl pyrrolidinone and acetonitrile etc.,preferably DMF or DMA usually in the temperature range of 30° C.–100° C.preferably in the range of 60–90° C. The molar ratio of compound (I)verses the base is 1:10 preferably in the range of 1:1.5–2.5 and withsolvent dilution is in the range of 5–25 times over the compound (I)preferably in the range of 5–10 times. The reaction is optionallyaccompanied by adding the base in portions preferably 3–5 times.

DBU is 1,8 diazabicyclo [5.4.0] undec-7-ene

DMF is dimethyl formamide and

DMA is N,N-dimethyl acetamide.

This invention relates to novel 1-[(4-methyl thio)phenyl]-2-(phenylacetoxy)-1-ethanone.

This invention also includes a process for the preparation of1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone which comprisesthe step of halogenating 4-methylthio acetophenone to produce1-[(4-methyl thio)phenyl]-2 halo ethanone, coupling said 1-[(4-methylthio)phenyl]-2-haloethanone with sodium salt of phenyl acetic acid toproduce 1-[(4-methyl thio)-2-(phenyl acetoxy)1-1-ethanone.

BEST METHOD OF CARRYING OUT THE INVENTION

Procedure for preparing 1-[(4-methyl thio)phenyl]-2-bromo ethanone isgiven hereinbelow:

4-methyl thio acetophenone (III) (250 g, 1.5 moles) and methanol (1.25lit) were charged into 3L reaction flask at RT. The resulting mixturewas cooled to 0 to 10° C. under stirring. Bromine (244 g, 1.5 moles) wasadded slowly over a period of 1 hour at 0 to 10° C. The reaction masswas maintained for 30 minutes for at 0 to 10° C. The reaction wasmonitored by TLC using 30% ethyl acetate in hexane and the statingmaterial absence was observed. The reaction mass pH was adjusted toneutral with NaHCO₃ (250 g) at 0 to 10° C. and the resulting mixture wasfiltered and washed with chilled methanol (100 ml) followed by chilledwater (250 ml). The material was dried at 50° C. under vacuum and theweight of the product obtained is 360 g (98%). The melting range forthis compound is 62–64° C.

¹H NMR (300 MHz. CDCl₃):δ 7.88–7.91 (d, 2H, ArH), 7.27–7.30 (d, 2H,ArH), 4.42 (s, 2H, CH₂Br), 2.54 (s, 3H, SCH₃)

Preparation of 1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanoneis given herein below:

Compound IV (250 g, 1.02 moles), phenyl acetic and sodium salt (169 g,1.06 moles) and Toulene (2.5 liters) were charged into dry 3L reactionflask at RT. 2.5 g of tetrabutyl ammonium iodide was added at roomtemperature. The resulting mixture was heated to 80 to 90° C. andmaintained for 3 hours at the same temperature. The reaction wasmonitored by TLC using 30% ethyl acetate in hexane and the absence ofstarting material observed. The reaction mass was cooled to roomtemperature, filtered, washed with 210 ml of toluene. The filtrate andthe washings were combined and distilled in vacuo at 50° C. followed byprecipitation with hexane (1 lit). The precipitated solid was filteredand washed with hexane (1 lit), dried thoroughly. The weight of theproduct obtained was 290 g (95%) and the melting range of the compound(I) was 73–74° C.

¹H NMR (300 MHz. CDCl₃):δ 7.79–7.82 (d, 2H, ArH), 7.25–7.37 (m, 7H,ArH), 5.32 (s, 2H, ArCH₂CO), 3.84 (s, 2H, COCH₂O), 2.53 (s, 3H, SCH₃).

The intermediate compound of formula II for the preparation of COX IIinhibitor may be prepared from the novel compound illustratedhereinabove by the following procedure:

Compound (I) (250 gms, 0.83 moles), Diisoproplyamine (210 gms, 2.07moles) and DMF (1.75 liters) were charges into 3L reaction flask at roomtemperature under nitrogen. The resulting mixture was heated to 60–70°C. The reaction was monitored by TLC, using 40% ethyl acetate in hexaneand the absence of the starting material was observed. The reaction massdiluted with 7 liters of ice water and neutralised with 10 NHCl (250 ml)under stirring and the resulting mixture was filtered and washed withwater (5 lit.) and dried. The crude product was dissolved in 2 liters oftoluene and the resulting mixture was heated to 80 to 90° C., 5 gram ofactivated carbon was added to the toluene solution and the mass wasfiltered. The toluene mother liquor was concentrated to 200 ml, cooled,filtered and the product was washed with 100 ml of toluene. The materialwas dried under vacuum and the weight of the product obtained was 225 g(95%). The melting range of the product was 141–142° C.

¹H NMR (300 MHz. CDCl₃):δ 7.39–7.44 (m, 5H, ArH), 7.23–7.28 (d, 2H,ArH), 7.15–7.18 (d,2H, ArH), 5.18 (s, 2H, CH₂), 2.49 (s, 3H, SCH₃).

1. 1-[4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone of the formulaI


2. A process wherein the compound of claim 1 is subjected to anintramolecular condensation in the presence of at least one organic orinorganic base so as to produce compound II


3. A process for the preparation of 1-[4-methylthio)phenyl]-2-(phenylacetoxy)-1-ethanone, the process comprisinghalogenating 4-methyl thio acetophenone at a temperature of forapproximately 0 to 20° C. to produce 1-[(4-methylthio)phenyl]-2-haloethanone, and coupling said 1[(4-methylthlo)phenyl]-2-haloethanone in presence of a base and optionally acatalyst selected from tetraalkyl ammonium halides and tricaprylylmethyl ammonium chloride in a solvent at a temperature of approximately40 to 100° C. with a sodium salt of phenyl acetic acid to produce1[((4-methylthio)phenyl]-2-(phenyl acetoxy)-1-ethanone.
 4. The processof claim 3, wherein halogenating comprises preparing 1[-((4-methylthio)phenyl]-2-bromoethanone by brominating methyl thio acetophenone andconverting said bromoethanone into 1-[(4-methylthio)phenyl]-2-(phenylacetoxy)-1-ethanone by coupling with phenyl acetic acid in a solution ofsodium salts.
 5. The process of claim 3 further comprising at least onephase transfer catalyst selected from tetrabutyl ammonium chloride,tetrabutyl ammonium bromide and tetrabutyl ammonium iodide.
 6. Theprocess of claim 3 wherein the solvent comprises toluene and atemperature of approximately 80–100° C.
 7. The process of claim 5,wherein said catalyst is present in approximately from 0.005 to 0.008molar equivalents of the 4-methyl thio acetophenone.